Presently, there is no predictive test for the development of glomerular disorders, and diagnosis is based on kidney biopsies, a very invasive diagnostic procedure. As an example, there is no predictive test for recurrent focal segmental glomerulosclerosis (FSGS) after a kidney transplant. FSGS accounts for up to 20% of end-stage renal disease (ESRD) and is the most common progressive glomerular disorder affecting the pediatric population. Although renal transplantation remains the best treatment option for patients with FSGS reaching ESRD, recurrent FSGS after transplantation occurs in 30-70% of the patients and markedly affects graft survival. The ability to predict which patients are at high risk for recurrent disease remains a challenge. As a second example, although 20-40% of patients with diabetes will develop diabetic nephropathy (DN), the identification of those patients at risk remains elusive.
The ability to predict the development of proteinuria and glomerular disorder in any primary or systemic illnesses that can affect the kidney is elusive (e.g., lupus, HIV, hepatitis, hemathological disorders, sarcoidosis). Similarly, no methodology exists for predicting if family members of patients with a non-genetic proteinuric glomerular disorder are at risk to develop the disorder. A prediction assay is also lacking for patients undergoing a kidney transplant to determine the risk for the development of kidney disease after kidney transplant (e.g., transplant glomerulopathy, rejection, allograft nephropathy, recurrence of the primary disease). Furthermore, for any renal (kidney) disease and/or glomerulopathy that can be either idiopatic (e.g., Membranous, minimal change, IgA, Membranoproliferative, FSGS, paucimmune glomerulonephritis), genetic (e.g., FSGS, storage disorders, Alport's) or secondary to a systemic illness (e.g., lupus, diabetes, HIV, hepatitis, hemathological disorders, sarcoidosis, other autoimmune disorders), the ability to predict what are the better treatment strategies for a specific patient is unrealized.
Proteinuria, kidney injury, renal failure and renal-related conditions contribute significantly to morbidity and mortality of affected patients. Proteinuric renal failure and/or kidney injury is often the result of local or systemic illnesses that affect the function of key elements of the glomerular filtration barrier of the kidney, a complex cellular structure that under physiological conditions prevents the leakage of protein from the blood side to the urinary side1. Although glomerular disease is the most common cause of pathological proteinuria, proteinuria can also be the result of tubular dysfunction or protein overflow. Among the three major components of the glomerular filtration barrier (endothelial cells, glomerular basement membrane and podocytes), the podocyte is a highly specialized cell that is usually affected in the early phases of proteinuric glomerular disorder as a result of diverse insults (e.g., systemic illnesses, autoimmune diseases, infectious diseases, toxic agents, drugs and others). These insults cause podocyte actin cytoskeleton remodeling and lead to clinically relevant proteinuria. Clinically relevant proteinuria is generally defined as urinary excretion of more than 150 mg of protein per 24 h or 150 mg/g creatinine on a spot urine sample or as urinary excretion of albumin of more than 30 mg per 24 h or 30 mg/g creatinine on a spot urine sample. Podocyte injury is also an important feature of DN, which is the most common cause of end stage renal disease in the United States. As proteinuric chronic kidney disease represents a growing epidemic despite available treatments, there is a need for the development of new drugs or of new indications for existing molecules and compounds.